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Hindawi Publishing Corporation

International Journal of Hepatology


Volume 2013, Article ID 484903, 13 pages
http://dx.doi.org/10.1155/2013/484903

Review Article
Hepatic Manifestations in Hematological Disorders

Jun Murakami1 and Yukihiro Shimizu2


1
The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama,
Toyama 930-0194, Japan
2
Gastroenterology Unit, Takaoka City Hospital, Toyama 933-8550, Japan

Correspondence should be addressed to Yukihiro Shimizu; rsf14240@nifty.com

Received 23 October 2012; Revised 11 February 2013; Accepted 11 February 2013

Academic Editor: Stephen D. H. Malnick

Copyright © 2013 J. Murakami and Y. Shimizu. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Liver involvement is often observed in several hematological disorders, resulting in abnormal liver function tests, abnormalities
in liver imaging studies, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and
hepatosplenomegaly are often seen mimicking liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver
and may demonstrate abnormal liver function test results accompanied by hepatosplenomegaly or formation of multiple nodules
in the liver and/or spleen. These cases may further evolve into fulminant hepatic failure.

1. Introduction jaundice, history of pigmented (bilirubin) gallstones, and


splenomegaly. Mild hepatomegaly can also occur [4].
Hepatologists or general physicians sometimes encounter
hepatic manifestations of various hematologic disorders in
daily practice, including various abnormalities in liver func- 2.1.3. Liver Function Tests in HA. In hemolysis, serum lactate
tion tests or imaging studies of the liver. Some hematologic dehydrogenase (LDH) levels (specifically the LDH1 and
disorders also mimic liver diseases. While review articles LDH2 isoforms) increase because of lysed erythrocytes [4].
regarding hematologic disorders and liver diseases have been Serum aspartate transaminase (AST) levels are also mildly
published previously [1–3], we also review more recent topics elevated in hemolysis, with the LDH/AST ratio mostly over
in this paper. 30 [7]. Total bilirubin levels can uncommonly exceed 5 mg/dL
if hepatic function is normal, except in the case of acute
hemolysis caused by sickle cell crisis. Liver dysfunction can
2. Red Blood Cell (RBC) Disorders also be caused by blood transfusion for anemia in sickle cell
disease (SCD) and thalassemia [1, 3].
2.1. Hemolytic Anemia (HA)
2.1.4. Hemolysis in Liver Disease. Hemolysis can be caused by
2.1.1. Classification according to the RBC Destruction Site.
either abnormalities in the erythrocyte membranes (intrin-
When the RBC membrane is severely damaged, immediate
sic) or environmental (extrinsic) factors. Most intrinsic
lysis occurs within the circulation (intravascular hemolysis).
causes are hereditary, except for paroxysmal nocturnal hemo-
In cases of less severe damage, the cells may be destroyed
globinuria (PNH) or rare conditions of acquired alpha tha-
within the monocyte-macrophage system in the spleen, liver,
lassemia [4].
bone marrow, and lymph nodes (extravascular hemolysis)
Extrinsic HA is caused by immune or nonimmune
[4–6].
mechanisms. Extrinsic nonimmune HA is caused by systemic
diseases, including some infectious diseases and liver or renal
2.1.2. Clinical Presentation. Patients with HA typically diseases. Various liver diseases may induce HA, and the two
present with the following findings: rapid onset of anemia, major causes of extrinsic HA in patients with liver disease are
2 International Journal of Hepatology

destruction of RBCs in an enlarged spleen (hypersplenism) 2.3.1. Clinical Presentation. The clinical manifestations of
and acquired alterations in the red cell membrane (e.g., target PNH are primarily related to abnormalities in the hematopoi-
cells, acanthocytes, echinocytes, and stomatocytes). Liver etic function, HA, a hypercoagulable state, bone marrow
diseases, especially those caused by alcohol intoxication, hypoplasia or aplasia, and progression to myelodysplastic
induce severe hypophosphatemia [8–10], which presumably syndrome or acute leukemia [18].
results in low red cell adenosine triphosphate levels, leading
to red cell membrane fragility and spheroidicity. These 2.3.2. Diagnosis of PNH. PNH was indirectly diagnosed
red cells are easily trapped in the spleen because of their formerly on the basis of the sensitivity of PNH red cells to
reduced deformability. When excess alcohol consumption is be lysed by complement. The sucrose lysis test is used as a
the predominant cause, the condition rapidly improves when screening test, and diagnosis is confirmed by the Ham acid
alcohol consumption is stopped. hemolysis test [20–22]. However, detection of glycosylinos-
Zieve syndrome is a poorly understood entity charac- itol phospholipid-linked protein deficiency in PNH by flow
terized by fatty liver/cirrhosis, severe upper abdominal and cytometric analysis has been developed for diagnosis [23].
right upper quadrant pain, jaundice, hyperlipidemia, and HA
[11–13]. 2.3.3. PNH-Associated Liver Disease. One of the serious
complications of PNH is development of a hypercoagulable
2.2. Autoimmune HA (AIHA). AIHA is characterized by state and formation of thrombi. Thrombosis in PNH typically
increased breakdown of RBCs due to autoantibodies with or occurs in the intracranial, hepatic, or portal vessels. PNH
without complement activation. Diagnosis of AIHA includes is one of the most common causes of de novo presentation
a combination of clinical and laboratory signs of RBC of portal vein thrombosis and a rare cause of Budd-Chiari
hemolysis together with detection of autoantibodies and/or syndrome [24].
complement deposition on RBCs detected by the direct
antiglobulin test, also known as the direct Coombs test [14]. 2.4. Sickle Cell Disease (SCD). SCD is an autosomal reces-
In more than half of affected patients, AIHA is associated sive genetic disorder resulting from inheritance of the
with an underlying disease including some type of infectious hemoglobin S (Hb S) variant of the 𝛽-globin chain. The
disease, immune disorder, or lymphoproliferative disorder most severe form with homozygosity for Hb S (Hb SS) is
(secondary AIHA), whereas other patients do not have any called sickle cell anemia (SCA). Less severe forms possess
evidence of underlying disorders (idiopathic or primary heterozygosity for Hb S and C (Hb SC) or Hb 𝛽-thalassemia
AIHA) [15]. (Hb 𝛽-thal). The erythrocytes deform to a crescent shape
(sickling) prone to hemolysis, often forming clumps in the
2.2.1. Liver Function Tests in AIHA. Laboratory findings vasculature (vaso-occlusive crisis), causing organ damages
of AIHA are not different from those of other causes of [25].
hemolysis, that is, reduction in serum haptoglobin, indirect
bilirubinemia, and elevated levels of serum LDH (I > II 2.4.1. Hepatic Manifestation in SCD. The liver can be affected
predominant) and AST (mostly LDH/AST > 30). Serum by the disease with vascular complications from the sickling
total bilirubin uncommonly exceeds 5 mg/dL, and polyclonal process. Moreover, multiple transfusions required for treat-
hypergammaglobulinemia is often seen. ment could increase the risk of viral hepatitis, iron overload,
and development of pigmented gallstones, all of which may
2.2.2. Liver Failure in AIHA. Immunoglobulin (Ig)G anti- contribute to development of a liver disease called “sickle cell
bodies (rarely IgM antibodies) generally react with antigens hepatopathy” [26–28]. Acute abdominal pain and abnormal
on the RBC surface at body temperature and are thus liver function tests as well as jaundice can be caused by
referred to as “warm agglutinins,” whereas IgM antibodies acute sickle hepatic crisis, sickle cell intrahepatic cholestasis,
(rarely IgG type) react with antigens on the RBC surface cholecystitis, and choledocholithiasis with common bile duct
below body temperature and are thus referred to as “cold obstruction.
agglutinins.” Warm-reacting IgM antibodies may lead to
hepatic failure by in vivo autoagglutination [16]. A fatal case 2.4.2. Liver Function Tests in SCD. Liver function test abnor-
with primary AIHA presenting as acute liver failure has been malities are common in patients with SCD. Elevation in
reported [16]. The patient experienced recurrent episodes indirect bilirubin, LDH, and AST without other evidence of
of intravascular hemolysis. Despite corticosteroid therapy, liver disease is found in 72% of patients with SCA, which
splenectomy, and multiple blood transfusions, the patient is related to the hemolysis and/or ineffective erythropoiesis
eventually succumbed to liver failure. [29]. Total bilirubin concentrations are usually <6 mg/dL
but may double (<15 mg/L) during sickle hepatic crisis [30].
2.3. PNH. PNH is an uncommon type of acquired hemolysis, Serum ALT levels may more accurately reflect hepatocyte
which occurs in middle-aged adults [17, 18]. Patients present injury [29]. Serum alkaline phosphatase (ALP), predomi-
with dark urine (hemoglobinuria), usually the morning nantly bone derived, is commonly elevated [31].
samples. PNH has been proven to be an acquired clonal Acute elevation in serum aminotransferase can be seen
genetic disease caused by somatic mutation of the X-linked with hepatic ischemia in vaso-occlusive crisis, whereas
PIG-A gene in hematopoietic stem cells [19]. chronic liver dysfunctions are found in 9%–25% of the
International Journal of Hepatology 3

patients [29, 32], usually caused by coexisting hepatic dis- 3.2. The Antiphospholipid Antibody Syndrome (APS). The
eases, such as chronic hepatitis B or C, common bile duct antiphospholipid antibody syndrome (APS) or APLA syn-
obstruction, or alcohol consumption. drome is characterized by the presence of one of antiphospho-
lipid antibody (aPL) in the plasma and occurrence of any clin-
2.4.3. Hyperammonemia due to Zinc Deficiency in SCD. Low ical manifestations including venous or arterial thromboses,
zinc plasma levels are reported in 44% of SCD patients [33], or pregnancy morbidity.
which may lead to development of encephalopathy due to
hyperammonemia in cirrhotic patients with SCA that can be 3.2.1. Clinical Presentation. APS occurs either as a primary or
corrected by zinc administration [34]. secondary from underlying diseases such as systemic lupus
erythematosus (SLE). In a series of primary or secondary
2.4.4. Liver Imaging Studies in SCD. The CT findings of APS, deep vein thrombosis (DVT) (32%) thrombocytope-
patients with homozygous SCA reveal diffuse hepatomegaly. nia (22%), livedo reticularis (20%), stroke (13%) superficial
The spleen is usually small and atrophic and may have thrombophlebitis (9%), pulmonary embolism (9%), fetal loss
dense calcifications due to repeated splenic infarction. Dou- (8%), transient ischemic attack (7%) and hemolytic anemia
ble heterozygotes (Hb SC and Hb S𝛽-thal) usually have (7%) are often observed [40], and venous thromboses are
splenomegaly and may show infarcts, rupture, hemorrhage, more common than arterial thromboses [41, 42]. Although
or abscesses of the spleen. the most common sites where DVT occurs are the calf and
MRI may show decreased signal intensity in the liver and the renal veins, hepatic, axillary, subclavian, and retinal veins,
pancreas [35] due to iron deposition in the SCD patients cerebral sinuses, and the vena cava may also be involved.
receiving chronic transfusions [36–39]. Abdominal ultra-
sound can reveal gallstones or increased echogenicity of the 3.2.2. Hepatic Manifestation in APS. The liver involvement
liver and pancreas due to iron deposition [37]. may include hepatic or portal venous thrombosis, which
could result in Budd-Chiari syndrome, hepatic veno-
occlusive disease, hepatic infarction, portal hypertension
3. Coagulation Disorders and cirrhosis. [40, 43].
3.1. Disseminated Intravascular Coagulation (DIC). DIC is a 3.3. HELLP Syndrome. HELLP syndrome is defined by
systemic process causing both thrombosis and hemorrhage. hemolysis with a microangiopathic blood smear, elevated
The pathogenesis of DIC is primarily due to excessive pro- liver enzymes, and a low platelet count [44]. HELLP syn-
duction of thrombin, leading to widespread and systemic drome occurs in approximately 1 to 2 per 1000 pregnancies
intravascular thrombus formation. Major initiating factors and in 10 to 20 percent of women with severe preeclamp-
are the release or expression of tissue factor secondary to sia/eclampsia.
extensive injury to the vascular endothelium or enhanced
expression by monocytes in response to endotoxin and
3.3.1. Clinical Presentation. The most common clinical pre-
various cytokines. The most common causes of DIC are
sentation is abdominal pain [45], nausea, vomiting, and
sepsis, trauma and tissue destruction, cancer, and obstetrical
malaise, which may resemble viral hepatitis, particularly if the
complications.
serums AST and LDH are markedly elevated [46]. Hyperten-
sion and proteinuria are present in approximately 85 percent
3.1.1. Diagnosis of DIC. Diagnosis of DIC is suggested by the of the cases. Differential diagnosis includes acute fatty liver
history and symptoms, thrombocytopenia, and presence of of pregnancy (AFLP). Prolongation of the prothrombin time
blood smear microangiopathic changes. The diagnosis is con- activated partial thromboplastin time (aPTT), low glucose
firmed by laboratory tests that demonstrate evidence of both and elevated creatinine concentrations are more common in
increased thrombus generation (e.g., decreased fibrinogen) women with AFLP than those with HELLP.
as and increased fibrinolysis (e.g., elevated fibrin degradation
products or D-dimer).
3.3.2. Hepatic Manifestation in HELLP Syndrome. HELLP
syndrome and severe preeclampsia may be associated with
3.1.2. Hepatic Manifestation in DIC. Jaundice is common
hepatic manifestations, including infarction, hemorrhage,
in patients with DIC and may be due to liver injury and
and rupture.
increased bilirubin production secondary to hemolysis. In
addition, hepatocellular injury may be produced by sepsis
and hypotension. Common manifestations of acute DIC, 4. Cryoglobulinemia
in addition to bleeding, include thromboembolism and
dysfunction of the kidney, liver, lungs, and central nervous 4.1. Definition and Classification. Precipitates in serum at
system. In a series of 118 patients with acute DIC, hepatic dys- temperatures below 37∘ C referred to cryoglobulin (CG). CG
function was found in 19% [38]. Severe liver disease involves consists of immunoglobulin (Ig) and complement compo-
decreased synthesis of coagulation factors and inhibitors [39], nents [47], and the cryoglobulinemia refers to the presence of
fibrinolysis, fibrinogenolysis, and elevated levels of fibrin CG in a patient’s serum. There are three types of CG according
degradation products. Thrombocytopenia may be induced by to Brouet classification, which is based on the clonality of Ig
hypersplenism secondary to portal hypertension. [48]. Type I CG (monoclonal Ig) is usually associated with a
4 International Journal of Hepatology

hematologic malignancy such as Waldenstrom’s macroglob- lineages. Lymphoid neoplasms are divided into acute lym-
ulinemia or multiple myeloma. Type II CG (polyclonal and phoblastic leukemia/lymphoma derived from B or T lym-
monoclonal Ig) is often secondary to chronic infections such phoid progenitors, or ones derived from mature T or B
as hepatitic C or human immunodeficiency virus infection. lymphocytes including plasma cells. Histiocytic/dendritic cell
Type III CG (polyclonal Ig) is often secondary to systemic neoplasms are derived from antigen presenting cells or tissue
rheumatic diseases. macrophages. Rare cases can be unclassifiable to myeloid or
lymphoid lineage [62].
4.2. Clinical Presentation. Clinical features of Type I CG
(monoclonal Ig) include hyperviscosity syndrome due to
hematological malignancies. While Type II and III CGs 6. Myeloid Neoplasms
(mixed and polyclonal Ig, resp.) are present with “Meltzer’s
Chronic MPNs, also called myeloproliferative disorders,
triad” of palpable purpura, arthralgia, and myalgia, caused by
classically include chronic myeloid leukemia (CML), poly-
vasculitis in small- to medium-sized vessels [49].
cythemia vera (PV), essential thrombocythemia, and pri-
Secondary lymphoproliferative disorders occur in less
mary idiopathic myelofibrosis.
than 5 to 10 percent of patients in type II CG patients 5 to
10 years after diagnosis [50–52]. The primary malignancies
6.1. CML. CML is an MPN characterized by dysregulated
include B cell non-Hodgkin lymphoma, both intermediate-
production and uncontrolled proliferation of mature and
to-high grade lymphoma and low-grade lymphoma such as
immature granulocytes with normal morphology. The tumor
immunocytoma, mucosa-associated lymphoid tumors, and
cells are derived from a pluripotent hematopoietic stem cell
centrocytic follicular lymphoma. Among patients with hep-
having the acquired BCR-ABL1 fusion gene, usually through
atitis C-associated type II cryoglobulinemia, the incidence of
translocation between chromosomes 9 and 22, t(9; 22)(q34;
non-Hodgkin lymphoma is estimated to be 35-fold higher
q11), referred to as the Philadelphia (Ph) chromosome. BCR-
than that in the general population.
ABL1 induces leukemogenesis through kinase dependent
4.3. Cryoglobulinemia in HCV Infection. The pathogenesis and independent signaling pathways. The natural history of
of CG has been most studied in chronic HCV infection. B CML is variable from the chronic phase to the accelerated
cell hyperactivation may result from HCV infection into B phase or blast crisis, but the progression process is not fully
cells via the cell surface protein CD81 [53], chronic, antigen- understood [62].
nonspecific stimulation by macromolecular serum complexes
containing HCV, including HCV-IgG and HCV-lipoprotein 6.1.1. Clinical Symptoms and Hepatic Manifestation of CML.
[54, 55], or from an HCV antigen-specific mechanism [56], At presentation, 20%–50% of patients are asymptomatic.
resulting in expansion of specific B cell clones expressing the Laboratory findings include leukocytosis with immature cells
WA idiotype [57] or V(H)1-69 [58]. HCV particles are often of the granulocytic series and basophilia, mild anemia, and
found in the CG complexes, but CG development in hepatitis thrombocytosis. Symptoms include fatigue, malaise, sweat-
C infection does not necessarily require HCV virion or its ing, and weight loss. Abdominal pain and discomfort may
components [59]. occur in the left upper quadrant (sometimes referred to the
Among patients with HCV infection, the number of left shoulder), and early satiety due to splenomegaly with
circulating regulatory T cells was compared between patients or without perisplenitis and/or splenic infarction may be
with symptomatic and asymptomatic CG [60], and the mean present. Variable degrees of hepatomegaly are also observed.
levels of regulatory T cells were found to be significantly Tenderness over the lower sternum is sometimes present due
lower in patients with symptomatic HCV-associated CG than to expanding bone marrow, and bleeding episodes due to
asymptomatic subjects. platelet dysfunction are often encountered [63, 64].
In the chronic phase, approximately 50% of patients with
4.4. Hepatic Manifestation of Cryoglobulinemia. Hepatic CML show mild to moderate hepatomegaly at presentation,
manifestations have been reported as hepatomegaly, abnor- with no liver function abnormalities [65]. At the time of blas-
mal liver function tests, or abnormal liver biopsy in up to 90 tic crisis, however, liver sinusoidal infiltration by immature
percent possibly due to chronic hepatitis itself [61]. cells may lead to liver enlargement and elevated serum ALP
levels [66].

5. Hematological Neoplasms 6.2. PV. PV is one of the chronic MPNs, and the clinical
features include an increased red cell count, splenomegaly,
5.1. Classification of Neoplasms of Hematopoietic Origin. thrombocytosis and/or leukocytosis, thrombotic complica-
Neoplasms derived from hematopoietic and lymphoid tissues tions, erythromelalgia, or pruritus. On physical examination,
are classified according to their morphologic, immunophe- splenomegaly, facial plethora (ruddy cyanosis), and hep-
notypic, genetic, and clinical features and by the type of atomegaly can be seen in 70%, 67%, and 40% of patients,
originating cell lineage and differentiation stage according respectively [67]. Nonpalpable splenomegaly is recognized in
to the widely used and accepted World Health Organization most patients on imaging studies [68, 69].
classification system of 2001, which was updated in 2008 [62]. Gastrointestinal complaints are common in PV, with a
Myeloid neoplasms include chronic myeloproliferative high incidence of epigastric distress, peptic ulcers, and gastro-
neoplasms (MPNs), MDS, or acute leukemias with myeloid duodenal erosions on upper endoscopy [70]. These have been
International Journal of Hepatology 5

attributed to alterations in gastric mucosal blood flow due 7.1.1. Hepatic Manifestations of HL. Liver infiltration of malig-
to altered blood viscosity and/or increased histamine release nant cells has been reported in 14% of patients with HL.
from tissue basophils, although one study has indicated a Hepatomegaly is found in 9% of patients with disease stages
high incidence of positivity for infection with Helicobacter I-II and in 45% of patients with stages III-IV [88]. Mild
pylori [70]. While direct liver involvement is uncommon, elevation of aminotransferase and moderate elevation of ALP
some patients may present with acute or chronic Budd-Chiari can occur due to tumor infiltration or extrahepatic bile duct
syndrome [71]. obstruction [88]. Cholestasis can be caused by direct infil-
tration of lymphoma cells, extrahepatic biliary obstruction,
6.3. Primary Myelofibrosis (PMF). Primary myelofibrosis viral hepatitis, drug hepatotoxicity, or vanishing bile duct
(PMF) is a chronic, malignant hematologicdisorder charac- syndrome [89–91]. Approximately 3%–13% of patients with
terized by splenomegaly, leukoerythroblastosis, bone marrow HL present with jaundice [90]. Acute liver failure can be
fibrosis, and extramedullary hematopoiesis. caused by ischemia secondary to compression of the hepatic
sinusoids by infiltrating lymphoma cells [92, 93].

6.3.1. Hepatic Manifestation of PMF. At the time of PMF diag-


nosis, hepatomegaly is observed in 40%–70% of patients and 7.2. Non-Hodgkin Lymphoma (NHL). NHL has been clas-
splenomegaly in at least 90% [72–74]. Hepatosplenomegaly is sified by cell morphology as small to large cell type and
caused by marked extramedullary hematopoiesis, which may according to the natural history of the clinical aggressiveness
develop after splenectomy, especially in the liver [75, 76]. In of the disease as low, intermediate, or high grade.
a report of 10 patients with PMF, a significant increase in the
liver size and serum concentrations of ALP, bilirubin, and/or 7.2.1. Hepatic Manifestation of NHL. Lymphoma cell infil-
𝛾-GTP was seen in all of the patients who subsequently tration of the liver with hepatomegaly is more common in
developed acute liver failure, resulting in death 3-4 weeks NHL than in HL, with 16%–43% of cases showing hepatic
after splenectomy [76]. involvement [88]. Extrahepatic obstruction is also more
common in NHL than in HL, and hepatic infiltration is
6.3.2. Abnormal Liver Function Tests in PMF. Patients with more common in low-grade B-cell lymphomas than in high-
PMF may have nonspecific laboratory test abnormalities, grade lymphomas [94]. Acute hepatic failure can occur
including elevation in serum concentrations of ALP, LDH, in NHL as seen in HL [95], which is caused by sudden
uric acid, leukocyte ALP, and vitamin B12 [77, 78]. Increase ischemia related to massive infiltration of the sinusoids or
in ALP may be due to liver or bone involvement of the replacement of liver parenchyma by malignant cells [95].
disease, while increase in LDH may result from ineffective Although liver involvement in both HL and NHL may present
hematopoiesis. as acute hepatic failure [96–101], liver transplantation should
be avoided [102].
Acute liver failure due to lymphoma can be suspected in
6.4. MPNs and Portal Vein Thrombosis. MPNs can be an cases of acute onset of hepatic enlargement and lactic acidosis
uncommon cause of portal vein tyrosine kinase (V617F) different from other causes of liver failure [2, 103].
thrombosis with unexplained etiology [79–81]. JAK2 muta-
tion may be detected in such cases [82, 83].
7.2.2. Abnormal Liver Function Tests in NHL. Liver function
tests of NHL patients show mild to moderate elevation in
6.5. MPNs and Budd-Chiari Syndrome. A JAK2 mutation can
serum ALP [88]. Elevated level of serum LDH is also often
be found in almost all patients with PV and approximately 50
seen in patients with NHL, especially in highly aggressive
percent of patients with essential thrombocythemia (ET) or
type such as Burkitt or lymphoblastic lymphoma, reflecting
PMF. JAK2 (V617F) mutations have been described in 26 to
high tumor burden, extensive infiltration of the liver, and
59 percent of patients with Budd-Chiari syndrome without
coincident immune-mediated HA, which are associated with
apparent findings of MPNs [84–87]. These findings suggest
poor prognosis.
the presence of occult MPNs in some patients with so-called
“idiopathic” Budd-Chiari syndrome.
7.2.3. Imaging Studies of the Liver in NHL. Although diffuse
hepatosplenomegaly is commonly observed in patients with
7. Lymphoid Neoplasms indolent lymphomas, liver function is usually preserved
in NHL. On the other hand, discrete hepatic masses are
7.1. Hodgkin Lymphoma (HL). HL, formerly called Hodgkin’s more common in the highly aggressive subtypes [104, 105].
disease, is the first recognized lymphoid tumor, which usually However, not all focal liver lesions in patients with NHL are
arises in lymph nodes and spreads in a contiguous manner due to lymphoma. In a report of 414 consecutive patients with
via the lymphatic system. HL is histologically characterized NHL, only 39% of focal liver lesions detected at disease onset
by giant cells called Hodgkin/Reed-Sternberg (H/RS) cells, were due to NHL and 58% were benign [106], whereas 74%
most of which are transformed Epstein-Barr virus-positive B of lesions detected during followup were due to NHL and
cells present in a reactive cellular background composed of 15% were due to a malignancy other than NHL (e.g., hepato-
granulocytes, plasma cells, and lymphocytes. cellular carcinoma, metastatic tumor from other secondary
6 International Journal of Hepatology

malignancy). Ascites may be present and can be chylous in 7.6. Hepatosplenic T-Cell Lymphoma
cases of lymphatic obstruction.
7.6.1. Clinical Presentation. Hepatosplenic T-cell lymphoma
7.3. Primary Hepatic NHL. Primary NHL of the liver is a rare is a rare type of aggressive NHL associated with patients
condition, accounting for <1% of all extranodal lymphomas. receiving antitumor necrosis factor-alpha therapy and purine
Two-thirds of cases occur in men aged approximately 50 analogues to treat inflammatory bowel disease [128].
years. Presenting symptoms include abdominal pain, fever,
hepatomegaly, and abnormal liver function tests with eleva-
tion of LDH higher than that of ALT [107, 108]. The most 7.6.2. Hepatic Manifestation of Hepatosplenic T-Cell Lym-
common histological subtype of primary hepatic NHL is phoma. Clinical features include hepatosplenomegaly, fever,
diffuse large B-cell lymphoma, comprising 80%–90% of cases. weight loss, night sweats, pancytopenia, and peripheral lym-
This disease may present with nodules in the liver or diffuse phocytosis. Liver function tests are elevated in approximately
portal infiltration and sinusoidal spread [109]. 50% of patients with slight elevation in AST, ALT, or ALP.
Acute liver failure from primary hepatic lymphoma Serum LDH levels are also elevated in approximately 50% of
has been treated with liver transplantation and subsequent patients, ranging from mild to extremely high. Immunosup-
chemotherapy [110]. Although primary hepatic lymphoma pression, especially of T cells, by antitumor necrosis factor-
is rare, persistent inflammatory processes associated with alpha therapy and purine analogues may increase the risk of
HCV infection or autoimmune disease may play a role in the this disease [129].
lymphomagenesis of hepatic B cells [111].

7.7. Hemophagocytic Syndrome (HPS)


7.4. Primary Hepatosplenic NHL. Primary hepatosplenic dif-
fuse large B-cell lymphoma associated with HCV has been 7.7.1. Clinical Presentation. HPS is a condition presenting
reported [112], and fetal acute liver failure can also occur with systemic inflammatory symptoms such as fever, hep-
[113]. Although the etiological role of HCV in lymphoma is atosplenomegaly, cytopenias, and hemophagocytosis in bone
unknown, HCV-positive lymphomas tend to arise in extra- marrow, spleen, and lymph nodes [130, 131]. HPS is caused
nodal sites, especially in the liver, spleen, or salivary glands by hypercytokinemia, which is triggered by highly stimulated
where HCV resides and chronic infiltration of lymphocytes natural killer and cytotoxic T cells. The underlying disorders
occurs. include viral infections, usually the Epstein-Barr virus in
younger patients, rheumatic disorders, immunodeficiency
syndromes, and aggressive lymphomas [132]. An aggressive
7.5. Intravascular Diffuse Large B-Cell Lymphoma. Intravas- form of NK-cell lymphoma or intravascular lymphoma of
cular diffuse large B-cell lymphoma or intravascular lym- an Asian variant was reported to be complicated by HPS
phoma is an uncommon but important condition in patients [133]. HPS should be suspected if patients meet at least five
with rapidly presenting fever, rash, or ischemic, neurologic, of the following eight criteria: fever, splenomegaly, cytopenia,
or respiratory signs. With this condition, tumor cells usually hypertriglyceridemia, low fibrinogen level, hemophagocyto-
evolve exclusively within small vessels in the skin, brain, sis on bone marrow biopsy, low or absent NK cell activity, or
liver, or lung. Biopsies from these organs are required for a elevated levels of ferritin or soluble IL2 receptor [130].
histologic diagnosis.
Symptoms of fever, night sweats, and weight loss are
seen in 55%–85% of B-cell lymphoma patients [114, 115]. 7.7.2. Hepatic Manifestation of HPS. HPS can cause hep-
The organs affected differ according to the area. In Western atomegaly, jaundice with cholestasis, moderate transaminase
countries, symptoms related to the central nervous system elevation, hyperferritinemia, decreased hepatic synthetic
(39%) and skin (39%) are mostly commonly experienced function, and fulminant hepatic failure. Hepatotoxicity is
[114, 116, 117], whereas those involving the bone marrow caused by hemophagocytosis in the hepatic sinusoids and
(32%), liver (26%), and spleen (26%) are less common. In portal tracts or by focal hepatocellular necrosis [132].
Asia, symptoms related to involvement of the bone marrow
(75%), spleen (67%), and liver (55%) are more common
8. Leukemia
[118–121], whereas those involving the central nervous sys-
tem (27%) and skin lesions (15%) are less common [122].
Hemophagocytic syndrome has also been reported in a 8.1. Acute Leukemia
Japanese series (Asian variant) [120].
Diagnosis of intravascular large cell lymphoma can be 8.1.1. Clinical Presentation. Acute leukemias are neoplasms
established by random skin biopsy [123] or biopsy of organs originated from precursors of myeloid or lymphoid lineage
suspected to be involved; for example, biopsies of the liver if (rarely ambiguous lineage). Although ALL is the most com-
unexplained abnormal liver function tests are seen, lung if mon malignancy in children, the incidence is increased also
unexplained pulmonary symptoms are present, and brain if in the elderly. The incidence of AML increases with age and
unexplained neurological symptoms exist [124–127]. AML is the most common types of adult leukemias.
International Journal of Hepatology 7

8.1.2. Hepatic Manifestation of Acute Leukemia. Although 30 percent of all leukemias in the United States. Although
hepatic involvement in acute leukemia is usually mild and CLL lymphocytes resemble normal small lymphocytes in
silent at the time of diagnosis [134], a postmortem study morphology, they are activated clonal B cells at the stage
showed liver infiltration in >95% of acute lymphoblastic between pre-B and mature B cells. [141–143]. B-CLL lympho-
leukemia (ALL) cases and up to 75% of acute myeloid cytes are positive for B-cell-associated antigens (CD19, CD20,
leukemia (AML) cases [135]. In ALL, infiltration was con- CD21, and CD23) and CD5 and express extremely low levels
fined to the portal tracts, whereas in AML, infiltration of surface membrane immunoglobulins (IgM or both IgM
was observed in both portal tracts and sinusoids. Massive and IgD).
leukemic cell infiltration of the liver may present as fulminant
hepatic failure [136]. In patients with acute leukemia, drug- 8.5.2. Clinical Staging of CLL. The natural history of CLL
induced liver injury and bacterial or fungal infections may is heterogenous. The staging systems that are widely used
also affect the liver. to predict patient prognosis and determine the therapeutic
strategies are the Rai system [144] and the Binet system [145].
8.1.3. AML and Hepatosplenomegaly. Palpable organomegaly
as a presentation of AML is uncommon, and significant
lymph node enlargement is rare in patients with AML. 8.5.3. Clinical Features of CLL. The most common physical
Marked hepatosplenomegaly is also uncommon; however, if finding is lymphadenopathy, which is present in 50 to 90
present, the patient is likely to have ALL or evolution of AML percent of the patients. The other lymphoid organ frequently
from a prior myeloproliferative disorder (blast crisis of CML). enlarged in CLL is spleen, being palpable in 25 to 55 percent
of the cases.
8.2. ALL in Children. At presentation, several abnormali-
ties, including hepatic dysfunction, coagulation abnormali- 8.5.4. Hepatic manifestation of CLL. Patients with CLL often
ties, hypercalcemia, hypocalcemia, hyperkalemia, and hyper- show mild to moderate liver enlargement at the time of initial
phosphatemia, may be noted in children with ALL [137]. diagnosis in 15%–25% of cases [145, 146]. The liver is usually
only mildly enlarged, ranging from 2 to 6 cm below the
right costal margin, with a span of dullness to percussion of
8.3. Precursor B-ALL/Lymphoblastic Lymphoma (LBL) in
approximately 10–16 cm. Upon palpation, the liver is usually
Adults. Precursor B-cell ALL is associated with decrease
nontender and firm with a smooth surface. An enlarged liver
in normal blood cells caused by replacement of the bone
in patients with CLL often displays extensive lymphocytic
marrow with tumor cells. The clinical presentations of
infiltration in the portal tracts with functional impairment of
patients include anemia, bleeding tendency, or susceptibility
the liver in late stages [147, 148].
to infections. B-symptoms such as fever, night sweats, and
weight loss are often present but may be mild. Hepatomegaly,
splenomegaly, or lymphadenopathy can be seen in up to half 8.6. Hairy Cell Leukemia (HCL)
of the adult patients upon presentation.
8.6.1. Clinical Presentation. Clinical presentation of HCL
includes the following [144, 149]: (1) abdominal fullness due
8.4. Precursor T-ALL/LBL. Precursor T-ALL/LBL originating to splenomegaly, which may cause spontaneous splenic rup-
from thymic precursor T-cells usually occurs in males aged ture [150], (2) systemic symptoms such as fatigue, weakness,
approximately 20 years old. The clinical presentation includes and weight loss without fever or night sweats, (3) bleeding
lymphadenopathy (50%) or an anterior bulky mediastinal tendency secondary to severe thrombocytopenia or recurrent
mass (50%–75%) [138]. Abdominal involvement is rare, but infections, and (4) asymptomatic splenomegaly or cytopenias
it could be found primarily in the liver and spleen. More which may be incidentally recognized, and the most common
than 80% of patients present with stage III or stage IV physical sign of HCL is palpable splenomegaly (80%–90%
disease, and almost 50% have B-symptoms and serum LDH of cases). Massive splenomegaly extending more than 8 cm
levels are usually elevated. Although the bone marrow is below the left costal margin is observed in 25% of cases.
frequently normal at presentation, approximately 60% of
patients develop bone marrow infiltration and a subsequent
8.6.2. Hepatic Manifestation of HCL. Hepatomegaly and
leukemic phase indistinguishable from T-cell ALL [139].
lymphadenopathy are not common in HCL, presenting in
approximately 20% and 10% of patients, respectively.
8.5. Chronic Lymphoid Leukemia (CLL)
8.6.3. Laboratory Findings. Most patients with HCL present
8.5.1. Clinical Presentation. Chronic lymphocytic leukemia with pancytopenia (60%–80%), anemia (85%), and throm-
(CLL) is one of the chronic lymphoproliferative disorders, bocytopenia and neutropenia (80%). Leukocytosis may be
characterized by a progressive accumulation of monoclonal present in 10%–20% of cases. Abnormal liver function tests
lymphoid cells. CLL is considered to be identical to small and hypergammaglobulinemia are seen in 20% of cases.
lymphocytic lymphoma (SLL), which is one of the indolent Leukemia cells often infiltrate the liver, in both the portal
non-Hodgkin lymphomas [62, 140]. CLL is the most common tracts and sinusoids, and liver enlargement has been observed
leukemia in Western countries, accounting for approximately in up to 40% of patients [151].
8 International Journal of Hepatology

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